van der Vorm E R, van der Zon G C, Möller W, Krans H M, Lindhout D, Maassen J A
Department of Medical Biochemistry, Sylvius Laboratory, Leiden, The Netherlands.
J Biol Chem. 1992 Jan 5;267(1):66-71.
In a patient with Leprechaunism, we have characterized a new mutation in the insulin receptor substituting Arg for Gly at position 31. The proband, the mother, and the maternal grandfather were heterozygous for the mutation. Fibroblasts of the proband show a strongly reduced number of high affinity insulin receptors on the cell surface, whereas fibroblasts of the healthy mother and grandfather show moderately reduced insulin receptor numbers. In the other family members neither the binding defect nor the Arg31 mutation was found. The Arg31-mutant receptor was overexpressed in Chinese hamster ovary cells. In these cells the mutant alpha beta-proreceptor was not proteolytically cleaved and no transport to the cell surface took place. The proreceptor was unable to bind insulin and to undergo autophosphorylation. In addition, the proreceptor was not recognized by monoclonal antibodies directed against conformation-dependent epitopes. These findings suggest that the Gly31 to Arg31 mutant is involved in the insulin receptor dysfunction seen in the Leprechaun patient. The mutation seems to alter the conformation of the receptor in such way that the transport of the proreceptor to the Golgi compartment, where proteolytical processing occurs, is inhibited.
在一名患有妖精貌综合征的患者中，我们鉴定出胰岛素受体的一个新突变，该突变在第31位将精氨酸替换为甘氨酸。先证者、其母亲和外祖父对此突变为杂合子。先证者的成纤维细胞在细胞表面显示高亲和力胰岛素受体数量大幅减少，而健康母亲和外祖父的成纤维细胞显示胰岛素受体数量中度减少。在其他家庭成员中，未发现结合缺陷和第31位精氨酸突变。第31位精氨酸突变受体在中国仓鼠卵巢细胞中过表达。在这些细胞中，突变的αβ前体受体未被蛋白水解切割，也未发生向细胞表面的转运。前体受体无法结合胰岛素，也无法进行自身磷酸化。此外，前体受体未被针对构象依赖性表位的单克隆抗体识别。这些发现表明，第31位甘氨酸到精氨酸的突变与妖精貌患者中所见的胰岛素受体功能障碍有关。该突变似乎以这样一种方式改变受体构象，即前体受体向发生蛋白水解加工的高尔基体区室的转运受到抑制。
